The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut

Abstract

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H1R) antagonists, which are used to control allergic inflammation, antagonists at H2R, which therapeutically decrease gastric acid release, and an antagonist at H3R, which is indicated to treat narcolepsy. Ligands at H4R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H4R ligands so far. Nevertheless, pre-clinically, H4R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H1R, H2R, and H3R do not provide an effect on inflammation, supporting the idea that H4R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H4R in inflammatory and inflammation-associated diseases of the gut.

Virtual Target Construction for Discovery of Human Histamine H4 Receptor Ligands Employing a Structure-Based Virtual Screening Approach

“…Considering the importance of hHRH4, especially on inflammation diseases, rheumatoid arthritis, asthma, dermatitis, and psoriasis [20], it is relevant to explore the main aspects of hHRH4. Exploring the receptor as a target for therapy in the future involves the receptor's active site, molecular modeling, and ligand exploration [21].…”

Evidence-based pathogenesis and treatment of ulcerative colitis: A causal role for colonic epithelial hydrogen peroxide

“…The third component, cromolyn sodium, is a mast cell stabilizer that inhibits the secretion of histamine by mast cells, which accumulate in large amounts at sites of tissue injury in UC[ 242 - 244 ]. Mast cells are significantly activated in UC and undergo intense degranulation resulting in the secretion of significantly greater amounts of histamine that is concentrated at sites of colonic inflammation in UC[ 245 - 248 ]. Rectal biopsies of patients with UC contained significantly higher amounts of histamine compared to normal controls[ 249 , 250 ].…”

“…Rectal biopsies of patients with UC contained significantly higher amounts of histamine compared to normal controls[ 249 , 250 ]. Histamine is degraded by diamine oxidase (EC 1.4.3.22) whose activity is especially high in the intestinal mucosa and the inflammatory field with H 2 O 2 being the product of this reaction[ 245 , 251 , 252 ]. Thus, cromolyn prevents histamine from being secreted from mucosal mast cells, which precludes its conversion to H 2 O 2 that can significantly contribute to the intensity and persistence of colonic inflammation in UC.…”

Basal Serum Diamine Oxidase Levels as a Biomarker of Histamine Intolerance: A Retrospective Cohort Study

“…Food intolerance is receiving increasing attention both from research [ 3 , 4 ] and in routine allergy clinical practice possibly due to the many and heterogenous overlapping symptoms with other clinical conditions. The term histamine intolerance (HIT) refers to a complex disorder of controversial definition [ 4 , 5 , 6 , 7 ], characterized by pseudo-allergic symptoms encompassing post-prandial malaise, diarrhea, and meteorism along with cutaneous manifestations, such as urticaria and itch, as well as vasomotor disturbances leading to hypotension, tachycardia, flushing, rhino-conjunctival symptoms, and headache [ 8 , 9 , 10 , 11 , 12 , 13 ]. HIT is supposed to be caused by an imbalance between histamine intake and catabolism [ 14 ].…”

“…The diagnostic work-up of HIT still remains challenging, uncertain, and time-consuming as well as frequently leading to misdiagnosis. As a consequence of this, the prevalence of HIT is underestimated, also in light of the high prevalence of potential confounders, such as food allergy, irritable bowel syndrome, lactose intolerance, and non-celiac gluten sensitivity, which may coexist with or constitute alternative diagnoses to HIT [ 6 , 12 , 13 , 18 , 19 , 20 ]. At present, the diagnosis of HIT is mostly achieved clinically either by the exclusion of other conditions and by a beneficial response to low-histamine diet [ 4 , 21 , 22 , 23 ] and/or DAO supplementation [ 24 , 25 ].…”